Pursuing the concept of translational research, we plan to bring preclinical observations to the care of patients who undergo allogeneic blood or bone marrow transplantation (BMT). Project I addresses three important areas in allogeneic BMT: graft-versus-host disease (GVHD), fungal infections and leukemic recurrence. To this end five exploratory clinical trials are proposed, building to a considerable extent on new concepts and preclinical information derived from research performed with support from this Program Project Grant. The first three specific aims of Project I focus on GVHD, namely the prevention of acute GVHD (Aim 1), treatment of acute GVHD (Aim 2) and treatment of chronic GVHD (Aim 3). Aim 1 is a phase II trial using low density percoll fractionated cells obtained from G-CSF "mobilized" peripheral blood progenitor cells as the source of allogeneic grafting. This cell processing technique results in a graft which is enriched for CD34+ progenitor cells and double negative (CD3+CD4-CD8-) T-cells and is relatively depleted of mature (CD4+ or CD8+) T-cells. Aim 2 is a phase I study of an amino acid polymer which binds to MHC class II molecules and will be used for treatment of acute GVHD. This polymer binds to antigen presenting cells and prevents the stimulation of responding T-cells. In Aim 3 we plan to test the immunosuppressive agent rapamycin in the treatment of chronic GVHD. In this study we will measure the pharmacokinetics of rapamycin and observe for its synergy with cyclosporine. Research in Aim 4 focuses on prevention of fungal infections. Specifically, we propose to perform a pharmacokinetics study of the anti-fungal drug, itraconazole, in a new liquid formulation (in cyclodextrin) which allows enhanced enteric absorption. Aim 5 addresses the problem of leukemic recurrence. We plan to test a novel method of immunotherapy based on cytokine induced killer (CIK) cells for the treatment of post-transplant relapse of the underlying hematologic malignancy. Progress in each of these three areas: GVHD, fungal infections and leukemic recurrence are important for the improved outcome of allogeneic BMT. If successful, these studies will serve as the basis for future randomized studies comparing these novel approaches to the best treatment available at the time when the next studies are initiated. The phase III studies will be carried out jointly at Stanford University and at the City of Hope National Medical Center. Finally, Project I will serve as a clinical resource for the other subprojects.